Serotonin (5-Hydroxytryptamine; 5-HT) receptors play a critical role in many physiological and behavioral functions in humans and animals (Hannon et al., 2008). These functions are mediated via 15 subtypes of 5-HT receptors (Hoyer et al., 2002). One of the recent additions to the serotonin receptors superfamily constitute 5-HT6 subtype, which via stimulating adenyl cyclase increases the cAMP intracellular level (Ruat et al., 1993; Schoeffter and Weaber, 1994).
The results of the autoradiographic and immunohistochemical studies, as well as mRNA hybridization experiments, revealed that 5-HT6 receptors were almost exclusively found in the central nervous system (CNS), displaying the highest density in the olfactory tubercle, cortex, striatum, nucleus accumbens and hippocampus (Kohen et al., 1996; Gerard et al., 1997; Ward et al., 1995).
Much of the recent interest in the 5-HT6 receptor results from the fact that several psychotropic agents display high affinity for 5-HT6 receptor and show antagonistic properties at these sites (Monsma et al., 1993). These compounds include amitriptyline, clozapine, quetiapine, olanzapine, sertindole. However, they display multitarget profile.
The results of the in vivo tests published so far have indicated that the 5-HT6 antagonists may evoke antidepressant and antianxiolytic responses in the animal models. As it was demonstrated by Wesotowska et al. compound SB-258585 displayed an antidepressant-like effect in the forced swim test in rats and anxiolytic-like effect in the conflict drinking test in rats (Wesotowska and Nikiforuk, 2007a). Other 5-HT6 antagonits, i.e. SB-399885, and SB-271046 also produced antidepressant-like activity in the forced swim test in rats (Hirano et al., 2009). Moreover, SB-399885 showed antianxiety-like effect in the conflict drinking (Vogel) test and an elevated plus maze test performed in rats (Wesotowska and Nikiforuk, 2007b).
The investigation of the potential role of 5-HT6 receptors in schizophrenia, conducted in the standard models of this disorder, revealed that 5-HT6 antagonists do not seem probable to display antipsychotic action (Pouzet et al., 2002). However, such compounds improve learning and memory in animal models, including novel object discrimination (King et al., 2004), Morris water maze learning (Rogers and Hagan, 2001) and attention set shifting (Rodefer et al., 2008). These results suggest that 5-HT6 antagonist might be useful for the treatment of cognitive deficits in schizophrenia and other cognitive disorders such as Alzheimer's disease.
The pharmacological studies of 5-HT6 ligands allowed observing interaction of the 5-HT6 modulators and other brain neurotransmitters, mainly acetylcholine (Ach) and glutamate (Glu). The 5-HT6 receptor antagonists have been shown to increase the acetylcholine transmission (Bentley et al., 1999; Riemer et al., 2003). Other studies have also presented that SB-271046, a 5-HT6 receptor antagonist, increases the level of glutamate in the cortex and hippocampus (Dawson et al., 2001), while application of a 5-HT6 receptor agonist WAY-466 leads to the hippocampal glutamate level decrease (Schechter et al., 2004). Taking into account the role of Ach and Glu in the learning and memory, these results might suggest that 5-HT6 receptors may impact the cognitive processes, which are often disturbed in the affective disorders and neurodegenerative diseases (Mitchell and Neumaier, 2005; Upton et al., 2008).
In the last years, the 5-HT6 receptor agents were reported to reduce the food intake in rats, thus suggesting that the 5-HT6 receptors modulators might be of potential use in the feeding disorders like obesity, anorexia and bulimia (Heal et al., 2008). As the current pharmacological approaches to the obesity treatment are not effective enough, these observations make the 5-HT6 receptors a promising molecular target for a new anti-obesity agents. These seems important, since obesity—characterized by an increase in body fat content resulting in excess body weight above accepted norms—is the most prevalent nutritional disorder in the western world. Importantly, it leads to increased mortality due to increased incidences of diseases such as cardiovascular, digestive, respiratory diseases, and type-2 diabetes.
Concluding, 5-HT6 selective agents have been identified as potentially useful in the treatment or prophylaxis of certain disorders of the central nervous system such as Parkinson's disease, schizophrenia, anxiety depression, maniac depression, obsessive compulsive disorders, mood disorders, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, neurodegenerative disorders characterized by impaired neuronal growth, panic attacks, epilepsy, attention deficit hyperactivity disorder (ADHD), withdraw from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, and pain. 5-HT6 ligands are also expected to be useful in the treatment or prophylaxis of obesity and type-2 diabetes.
The first selective 5-HT6 receptors ligands were identified by the high throughput screening of the compound libraries, which resulted in the selection of the antagonist I-SB-271046 (Formula (I)). It was the first 5-HT6 receptor agent that entered clinical trials for cognitive impairment in schizophrenia and Alzheimer's disease.
In the same time, a series of tryptamine derivatives based around EMDT was reported as 5-HT6R agonists. In a next move, arylsulfonamide derivatives of indole and indole-like structures were designed. It was found, that compound MS-245 displayed high affinity for 5-HT6 receptors and high selectivity over other monoaminergic receptors (Formulas (II)-(III)). Moreover, an introduction of the sulfonamide moiety switched the functional profile from agonistic to antagonistic one.

Since that time, several 5-HT6 ligands possessing sulfonyl or sulfonamide moiety have been developed. Chemically, they might be divided into two main groups. The first one consists in the indole and indole-like based structures. Among them PF-05212365 is currently under clinical development for the treatment of cognitive deficits in schizophrenia and Alzheimer disease (Formula (IV)).
The second group comprises arylpiperazine derivatives, containing one or more condensed aromatic rings. PRX-07034 belongs to monoarylpiperazine derivatives modified with sulfonyl moiety (Formula (V)). Currently it is investigated under clinical trials for cognition and suppression of the food intake. Other arylpiperazine derivatives with planar aromatic systems, e.g. SB-742457 and R-1485 are the subject of clinical trials for cognitive impairment in schizophrenia and Alzheimer's disease (Formulas (VI)-(VII)).

It is worth noting that the above mentioned structures, adapt in the pharmacophore models for 5-HT6 receptors antagonists, independently developed by Pullagurla (Pullagurla et al., 2004) and López-Rodriguez (López-Rodriguez et al. 2005). The key elements proposed in these models are the two hydrophobic regions, double hydrogen bond acceptor (mainly sulfonyl or sulfonamide moiety) and the basic center of the molecule.
Although the sulfonyl or sulfonamide group may be replaced by its amide or alkyl bioisoster or carboxamide group (Cole et al., 2003; WO2005030724), arylsulfonyl and arylsulfonamide derivatives remain an important class of 5-HT6 ligands. Several patent publication e.g. U.S. Pat. No. 8,003,670, U.S. Pat. No. 6,423,717, U.S. Pat. No. 7,960,374 B2, US 2009/0069337 A1, WO 2011/044134 A1, EP 2069310 B1, disclose several classes of arylsulfonamides, and claim their potential application in the treatment of CNS disorders related to disturbance of 5-HT6 receptor functions.
The goal of the present invention relates to providing potent and selective 5-HT6 antagonists based on a pyrroloquinoline core structure, as compounds useful for the treatment of certain CNS disorders.
Since many years the pyrrolo[3,2-c]quinoline system has been widely used as a central core of biologically active compounds possessing antitumor (Helissey et al., 1987), hypotensive (Wright et al., 1971) and anti-inflammatory properties (U.S. Pat. No. 5,216,162). Pyrroloquinoline-derived heterocycles were also shown to inhibit the gastric (H+/K+)-ATPase, an enzyme responsible for secretion of acid into the gastric lumen (Brown et al., 1990).
The antisecretory activity of pyrrolo[3,2-c]quinolines was found beneficial in the treatment of the gastric ulcer and was disclosed in the international patent publication WO 00/01696 (Formulas (VIII)-(IX)).

Furthermore, derivatives containing pyrrolo[3,2-c]quinoline core unit might act as inhibitors of kynurenine-3-hydroxylase (KYN-OH) enzyme, which is involved in the tryptophan metabolism and leads to the accumulation of the potent neurotoxic quinolinic acid. It is believed that selective inhibition of KYN-OH might play a rote in the neuronal protection (Heidempergher et al., 1999). The synthesis of pyrrolo[3,2-c]quinoline derivatives along with their use for the prevention and treatment in the neurodegenerative diseases, revealed by such mechanism of action, was the subject of the international patent application WO 98/05660 (Formulas (X)-(XI)).

It is worth noting that pyrrolo[2,3-f]quinolines were reported to show affinity for 5-HT2A, 5-HT2B and 5-HT2C receptors. Patent publication U.S. Pat. No. 6,365,598 B1 discloses series of differently substituted pyrroloquinolines as agonists and antagonists of 5-HT2A and 5-HT2C sites and their application in the treatment of CNS disorders, including obesity, schizophrenia, depression, anxiety, migraine, sexual disorders, pain and gastrointestinal dysfunctions (Formula (XII)).

Moreover, their structural analogs, pyrroloquinoxaline derivatives, have been developed as potent 5-HT3 receptors agonists with potential analgesic-like properties.
Recently, Benakki et al. reported on a synthesis of N-methyl-pyrrolo-[3,2-c]quinoline derivatives of general formula (XIII) (Benakki et al., 2008).
